Publications by authors named "Tony Davis"

18 Publications

  • Page 1 of 1

Screening and characterization of polyhydroxyalkanoate granules, and phylogenetic analysis of polyhydroxyalkanoate synthase gene PhaC in cyanobacteria.

J Phycol 2020 Dec 22. Epub 2020 Dec 22.

Scripps Institution of Oceanography, University of California, San Diego, La Jolla, California, 92093-0202, USA.

Using Nile Red and BODIPY 493/503 dye-staining and fluorescence microscopy, twenty cyanobacterial strains, including ten commercially available strains and ten environmental isolates from estuaries, freshwater ponds, and lagoons, were screened for the accumulation of ecologically important and potentially biotechnologically significant carbon storage granules such as polyhydroxyalkanoates (PHA). Dye-staining granules were observed in six strains. Three Synechocystis, spp. strains WHSYN, LSNM, and CGF-1, and a Phormidium-like sp. CGFILA were isolated from environmental sources and found to produce granules of polyhydroxyalkanoate (PHA) according to PHA synthase gene (phaC) PCR screening and H NMR analyses. The environmental isolate, Nodularia sp. Las Olas and commercially available Phormidium cf. iriguum CCALA 759 displayed granules but screened negative for PHA according to phaC PCR and H NMR analyses. Partial polyhydroxyalkanoate synthase subunit C (phaC) and 16S rRNA gene sequences obtained from the PHA-accumulating strains and analyzed alongside publicly available phaC, phaE, 16S rRNA, and 23S rRNA data help in understanding the distribution and evolutionary history of PHA biosynthesis within the phylum Cyanobacteria. The data show that the presence of phaC is highly conserved within the genus Synechocystis, and present in at least one isolate of Phormidium. Maximum likelihood analyses and cophylogenetic modeling of PHA synthase gene sequences provide evidence of a recent horizontal gene transfer event between distant genera of cyanobacteria related to Pleurocapsa sp. PCC 7327 and Phormidium-like sp. CGFILA. These findings will help guide additional screening for PHA producers, and may explain why some Phormidium species produce PHAs, while others do not.
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http://dx.doi.org/10.1111/jpy.13123DOI Listing
December 2020

Dynamic visualization of type II peptidyl carrier protein recognition in pyoluteorin biosynthesis.

RSC Chem Biol 2020 Apr 24;1(1):8-12. Epub 2020 Mar 24.

Department of Chemistry and Biochemistry, University of California-San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0358, USA.

Using a covalent chemical probe and X-ray crystallography coupled to nuclear magnetic resonance data, we elucidated the dynamic molecular basis of protein recognition between the carrier protein and adenylation domain in pyoluteorin biosynthesis. These findings reveal a unique binding mode, which contrasts previously solved carrier protein and partner protein interfaces.
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http://dx.doi.org/10.1039/c9cb00015aDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7723355PMC
April 2020

Interfacial plasticity facilitates high reaction rate of FAS malonyl-CoA:ACP transacylase, FabD.

Proc Natl Acad Sci U S A 2020 09 14;117(39):24224-24233. Epub 2020 Sep 14.

Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, CA 92093-0358;

Fatty acid synthases (FASs) and polyketide synthases (PKSs) iteratively elongate and often reduce two-carbon ketide units in de novo fatty acid and polyketide biosynthesis. Cycles of chain extensions in FAS and PKS are initiated by an acyltransferase (AT), which loads monomer units onto acyl carrier proteins (ACPs), small, flexible proteins that shuttle covalently linked intermediates between catalytic partners. Formation of productive ACP-AT interactions is required for catalysis and specificity within primary and secondary FAS and PKS pathways. Here, we use the FAS AT, FabD, and its cognate ACP, AcpP, to interrogate type II FAS ACP-AT interactions. We utilize a covalent crosslinking probe to trap transient interactions between AcpP and FabD to elucidate the X-ray crystal structure of a type II ACP-AT complex. Our structural data are supported using a combination of mutational, crosslinking, and kinetic analyses, and long-timescale molecular dynamics (MD) simulations. Together, these complementary approaches reveal key catalytic features of FAS ACP-AT interactions. These mechanistic inferences suggest that AcpP adopts multiple, productive conformations at the AT binding interface, allowing the complex to sustain high transacylation rates. Furthermore, MD simulations support rigid body subdomain motions within the FabD structure that may play a key role in AT activity and substrate selectivity.
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http://dx.doi.org/10.1073/pnas.2009805117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7533678PMC
September 2020

Structural basis for selectivity in a highly reducing type II polyketide synthase.

Nat Chem Biol 2020 07 4;16(7):776-782. Epub 2020 May 4.

Department of Biotechnology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan.

In type II polyketide synthases (PKSs), the ketosynthase-chain length factor (KS-CLF) complex catalyzes polyketide chain elongation with the acyl carrier protein (ACP). Highly reducing type II PKSs, represented by IgaPKS, produce polyene structures instead of the well-known aromatic skeletons. Here, we report the crystal structures of the Iga11-Iga12 (KS-CLF) heterodimer and the covalently cross-linked Iga10=Iga11-Iga12 (ACP=KS-CLF) tripartite complex. The latter structure revealed the molecular basis of the interaction between Iga10 and Iga11-Iga12, which differs from that between the ACP and KS of Escherichia coli fatty acid synthase. Furthermore, the reaction pocket structure and site-directed mutagenesis revealed that the negative charge of Asp 113 of Iga11 prevents further condensation using a β-ketoacyl product as a substrate, which distinguishes IgaPKS from typical type II PKSs. This work will facilitate the future rational design of PKSs.
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http://dx.doi.org/10.1038/s41589-020-0530-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7556716PMC
July 2020

Gating mechanism of elongating β-ketoacyl-ACP synthases.

Nat Commun 2020 04 7;11(1):1727. Epub 2020 Apr 7.

Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093-0358, USA.

Carbon-carbon bond forming reactions are essential transformations in natural product biosynthesis. During de novo fatty acid and polyketide biosynthesis, β-ketoacyl-acyl carrier protein (ACP) synthases (KS), catalyze this process via a decarboxylative Claisen-like condensation reaction. KSs must recognize multiple chemically distinct ACPs and choreograph a ping-pong mechanism, often in an iterative fashion. Here, we report crystal structures of substrate mimetic bearing ACPs in complex with the elongating KSs from Escherichia coli, FabF and FabB, in order to better understand the stereochemical features governing substrate discrimination by KSs. Complemented by molecular dynamics (MD) simulations and mutagenesis studies, these structures reveal conformational states accessed during KS catalysis. These data taken together support a gating mechanism that regulates acyl-ACP binding and substrate delivery to the KS active site. Two active site loops undergo large conformational excursions during this dynamic gating mechanism and are likely evolutionarily conserved features in elongating KSs.
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http://dx.doi.org/10.1038/s41467-020-15455-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7138838PMC
April 2020

Desert crossing strategies of migrant songbirds vary between and within species.

Sci Rep 2019 12 27;9(1):20248. Epub 2019 Dec 27.

Piedalbuccio, 20232, Oletta, France.

Each year, billions of songbirds cross large ecological barriers during their migration. Understanding how they perform this incredible task is crucial to predict how global change may threaten the safety of such journeys. Earlier studies based on radar suggested that most songbirds cross deserts in intermittent flights at high altitude, stopping in the desert during the day, while recent tracking with light loggers suggested diurnal prolongation of nocturnal flights and common non-stop flights for some species. We analyzed light intensity and temperature data obtained from geolocation loggers deployed on 130 individuals of ten migratory songbird species, and show that a large variety of strategies for crossing deserts exists between, but also sometimes within species. Diurnal stopover in the desert is a common strategy in autumn, while most species prolonged some nocturnal flights into the day. Non-stop flights over the desert occurred more frequently in spring than in autumn, and more frequently in foliage gleaners. Temperature recordings suggest that songbirds crossed deserts with flight bouts performed at various altitudes according to species and season, along a gradient ranging from low above ground in autumn to probably >2000 m above ground level, and possibly at higher altitude in spring. High-altitude flights are therefore not the general rule for crossing deserts in migrant songbirds. We conclude that a diversity of migration strategies exists for desert crossing among songbirds, with variations between but also within species.
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http://dx.doi.org/10.1038/s41598-019-56677-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6934701PMC
December 2019

Role of MyD88 in IL-1β and Ethanol Modulation of GABAergic Transmission in the Central Amygdala.

Brain Sci 2019 Dec 7;9(12). Epub 2019 Dec 7.

Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA.

Myeloid differentiation primary response protein (MyD88) is a critical neuroimmune adaptor protein in TLR (Toll-like receptor) and IL-1R (Interleukin-1 receptor) signaling complexes. These two pro-inflammatory families play an important role in the neurobiology of alcohol use disorder, specifically MyD88 regulates ethanol drinking, ethanol-induced sedation, and ethanol-induced deficits in motor coordination. In this study, we examined the role of MyD88 in mediating the effects of IL-1β and ethanol on GABAergic transmission in the central amygdala (CeA) of male mice using whole-cell patch-clamp recordings in combination with pharmacological (AS-1, a mimetic that prevents MyD88 recruitment by IL-1R) and genetic ( knockout mice) approaches. We demonstrate through both approaches that IL-1β and ethanol's modulatory effects at CeA GABA synapses are not dependent on MyD88. knockout potentiated IL-1β's actions in reducing postsynaptic GABA receptor function. Pharmacological inhibition of MyD88 modulates IL-1β's action at CeA GABA synapses similar to knockout mice. Additionally, ethanol-induced CeA GABA release was greater in knockout mice compared to wildtype controls. Thus, MyD88 is not essential to IL-1β or ethanol regulation of CeA GABA synapses but plays a role in modulating the magnitude of their effects, which may be a potential mechanism by which it regulates ethanol-related behaviors.
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http://dx.doi.org/10.3390/brainsci9120361DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6956324PMC
December 2019

Type II non-ribosomal peptide synthetase proteins: structure, mechanism, and protein-protein interactions.

Nat Prod Rep 2020 03;37(3):355-379

Department of Chemistry and Biochemistry, University of California, 9500 Gilman Drive, La Jolla, San Diego, California 92093-0358, USA.

Covering: 1990 to 2019 Many medicinally-relevant compounds are derived from non-ribosomal peptide synthetase (NRPS) products. Type I NRPSs are organized into large modular complexes, while type II NRPS systems contain standalone or minimal domains that often encompass specialized tailoring enzymes that produce bioactive metabolites. Protein-protein interactions and communication between the type II biosynthetic machinery and various downstream pathways are critical for efficient metabolite production. Importantly, the architecture of type II NRPS proteins makes them ideal targets for combinatorial biosynthesis and metabolic engineering. Future investigations exploring the molecular basis or protein-protein recognition in type II NRPS pathways will guide these engineering efforts. In this review, we consolidate the broad range of NRPS systems containing type II proteins and focus on structural investigations, enzymatic mechanisms, and protein-protein interactions important to unraveling pathways that produce unique metabolites, including dehydrogenated prolines, substituted benzoic acids, substituted amino acids, and cyclopropanes.
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http://dx.doi.org/10.1039/c9np00047jDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7101270PMC
March 2020

Modifying the Thioester Linkage Affects the Structure of the Acyl Carrier Protein.

Angew Chem Int Ed Engl 2019 08 2;58(32):10888-10892. Epub 2019 Jul 2.

Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, 92093-0358, USA.

At the center of many complex biosynthetic pathways, the acyl carrier protein (ACP) shuttles substrates to appropriate enzymatic partners to produce fatty acids and polyketides. Carrier proteins covalently tether their cargo via a thioester linkage to a phosphopantetheine cofactor. Due to the labile nature of this linkage, chemoenzymatic methods have been developed that involve replacement of the thioester with a more stable amide or ester bond. We explored the importance of the thioester bond to the structure of the carrier protein by using solution NMR spectroscopy and molecular dynamics simulations. Remarkably, the replacement of sulfur with other heteroatoms results in significant structural changes, thus suggesting more rigorous selections of isosteric substitutes is needed.
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http://dx.doi.org/10.1002/anie.201903815DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6663632PMC
August 2019

Active site labeling of fatty acid and polyketide acyl-carrier protein transacylases.

Org Biomol Chem 2019 05;17(19):4720-4724

Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0358, USA.

Metabolic engineering of fatty acids and polyketides remains challenging due to unresolved protein-protein interactions that are essential to synthase activity. While several chemical probes have been developed to capture and visualize protein interfaces in these systems, acyl carrier protein (ACP) transacylase (AT) domains remain elusive. Herein, we combine a mutational strategy with fluorescent probe design to expedite the study of AT domains from fatty acid and polyketide synthases. We describe the design and evaluation of inhibitor-inspired and substrate-mimetic reporters containing sulfonyl fluoride and β-lactone warheads. Moreover, specific active-site labeling occurs by optimizing pH, time, and probe concentration, and selective labeling is achieved in the presence of inhibitors of competing domains. These findings provide a panel of AT-targeting probes and set the stage for future combinatorial biosynthetic and drug discovery initiatives.
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http://dx.doi.org/10.1039/c8ob03229gDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6597490PMC
May 2019

Preparation, Assay, and Application of Chlorinase SalL for the Chemoenzymatic Synthesis of S-Adenosyl-l-Methionine and Analogs.

Methods Enzymol 2018 2;604:367-388. Epub 2018 Apr 2.

University of Illinois at Chicago, College of Pharmacy, and Center for Biomolecular Sciences, Chicago, IL, United States. Electronic address:

S-adenosyl-l-methionine (SAM) is universal in biology, serving as the second most common cofactor in a variety of enzymatic reactions. One of the main roles of SAM is the methylation of nucleic acids, proteins, and metabolites. Methylation often imparts regulatory control to DNA and proteins, and leads to an increase in the activity of specialized metabolites such as those developed as pharmaceuticals. There has been increased interest in using SAM analogs in methyltransferase-catalyzed modification of biomolecules. However, SAM and its analogs are expensive and unstable, degrading rapidly under physiological conditions. Thus, the availability of methods to prepare SAM in situ is desirable. In addition, synthetic methods to generate SAM analogs suffer from low yields and poor diastereoselectivity. The chlorinase SalL from the marine bacterium Salinispora tropica catalyzes the reversible, nucleophilic attack of chloride at the C5' ribosyl carbon of SAM leading to the formation of 5'-chloro-5'-deoxyadenosine (ClDA) with concomitant displacement of l-methionine. It has been demonstrated that the in vitro equilibrium of the SalL-catalyzed reaction favors the synthesis of SAM. In this chapter, we describe methods for the preparation of SalL, and the chemoenzymatic synthesis of SAM and SAM analogs from ClDA and l-methionine congeners using SalL. In addition, we describe procedures for the in situ chemoenzymatic synthesis of SAM coupled to DNA, peptide, and metabolite methylation, and to the incorporation of isotopes into alkylated products.
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http://dx.doi.org/10.1016/bs.mie.2018.02.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6625345PMC
April 2019

Design, synthesis, and biological evaluation of α-hydroxyacyl-AMS inhibitors of amino acid adenylation enzymes.

Bioorg Med Chem Lett 2016 11 16;26(21):5340-5345. Epub 2016 Sep 16.

Pharmacology Program, Weill Cornell Graduate School of Medical Sciences, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 422, New York, NY 10065, United States; Chemical Biology Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 422, New York, NY 10065, United States; Tri-Institutional Research Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 422, New York, NY 10065, United States.

Biosynthesis of bacterial natural-product virulence factors is emerging as a promising antibiotic target. Many such natural products are produced by nonribosomal peptide synthetases (NRPS) from amino acid precursors. To develop selective inhibitors of these pathways, we have previously described aminoacyl-AMS (sulfamoyladenosine) macrocycles that inhibit NRPS amino acid adenylation domains but not mechanistically-related aminoacyl-tRNA synthetases. To improve the cell permeability of these inhibitors, we explore herein replacement of the α-amino group with an α-hydroxy group. In both macrocycles and corresponding linear congeners, this leads to decreased biochemical inhibition of the cysteine adenylation domain of the Yersina pestis siderophore synthetase HMWP2, which we attribute to loss of an electrostatic interaction with a conserved active-site aspartate. However, inhibitory activity can be regained by installing a cognate β-thiol moiety in the linear series. This provides a path forward to develop selective, cell-penetrant inhibitors of the biosynthesis of virulence factors to probe their biological functions and potential as therapeutic targets.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5079767PMC
http://dx.doi.org/10.1016/j.bmcl.2016.09.027DOI Listing
November 2016

Genome-wide association study of 40,000 individuals identifies two novel loci associated with bipolar disorder.

Hum Mol Genet 2016 08 21;25(15):3383-3394. Epub 2016 Jun 21.

Institute of Human Genetics, University of Bonn, Germany.

Bipolar disorder (BD) is a genetically complex mental illness characterized by severe oscillations of mood and behaviour. Genome-wide association studies (GWAS) have identified several risk loci that together account for a small portion of the heritability. To identify additional risk loci, we performed a two-stage meta-analysis of >9 million genetic variants in 9,784 bipolar disorder patients and 30,471 controls, the largest GWAS of BD to date. In this study, to increase power we used ∼2,000 lithium-treated cases with a long-term diagnosis of BD from the Consortium on Lithium Genetics, excess controls, and analytic methods optimized for markers on the X-chromosome. In addition to four known loci, results revealed genome-wide significant associations at two novel loci: an intergenic region on 9p21.3 (rs12553324, P =  5.87 × 10   ; odds ratio (OR) = 1.12) and markers within ERBB2 (rs2517959, P =  4.53 × 10   ; OR = 1.13). No significant X-chromosome associations were detected and X-linked markers explained very little BD heritability. The results add to a growing list of common autosomal variants involved in BD and illustrate the power of comparing well-characterized cases to an excess of controls in GWAS.
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http://dx.doi.org/10.1093/hmg/ddw181DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5179929PMC
August 2016

General platform for systematic quantitative evaluation of small-molecule permeability in bacteria.

ACS Chem Biol 2014 Nov 8;9(11):2535-44. Epub 2014 Sep 8.

Pharmacology Program-Weill Cornell Graduate School of Medical Sciences, ‡Gerstner Sloan Kettering Summer Undergraduate Research Program, §Molecular Pharmacology & Chemistry Program and Tri-Institutional Research Program, Memorial Sloan Kettering Cancer Center , 1275 York Avenue, Box 422, New York, New York 10065, United States.

The chemical features that impact small-molecule permeability across bacterial membranes are poorly understood, and the resulting lack of tools to predict permeability presents a major obstacle to the discovery and development of novel antibiotics. Antibacterials are known to have vastly different structural and physicochemical properties compared to nonantiinfective drugs, as illustrated herein by principal component analysis (PCA). To understand how these properties influence bacterial permeability, we have developed a systematic approach to evaluate the penetration of diverse compounds into bacteria with distinct cellular envelopes. Intracellular compound accumulation is quantitated using LC-MS/MS, then PCA and Pearson pairwise correlations are used to identify structural and physicochemical parameters that correlate with accumulation. An initial study using 10 sulfonyladenosines in Escherichia coli, Bacillus subtilis, and Mycobacterium smegmatis has identified nonobvious correlations between chemical structure and permeability that differ among the various bacteria. Effects of cotreatment with efflux pump inhibitors were also investigated. This sets the stage for use of this platform in larger prospective analyses of diverse chemotypes to identify global relationships between chemical structure and bacterial permeability that would enable the development of predictive tools to accelerate antibiotic drug discovery.
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http://dx.doi.org/10.1021/cb5003015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4245172PMC
November 2014

Pharmacokinetic and in vivo efficacy studies of the mycobactin biosynthesis inhibitor salicyl-AMS in mice.

Antimicrob Agents Chemother 2013 Oct 15;57(10):5138-40. Epub 2013 Jul 15.

Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Mycobactin biosynthesis in Mycobacterium tuberculosis facilitates iron acquisition, which is required for growth and virulence. The mycobactin biosynthesis inhibitor salicyl-AMS [5'-O-(N-salicylsulfamoyl)adenosine] inhibits M. tuberculosis growth in vitro under iron-limited conditions. Here, we conducted a single-dose pharmacokinetic study and a monotherapy study of salicyl-AMS with mice. Intraperitoneal injection yielded much better pharmacokinetic parameter values than oral administration did. Monotherapy of salicyl-AMS at 5.6 or 16.7 mg/kg significantly inhibited M. tuberculosis growth in the mouse lung, providing the first in vivo proof of concept for this novel antibacterial strategy.
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http://dx.doi.org/10.1128/AAC.00918-13DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3811451PMC
October 2013

Tolerability of anal dysplasia screening.

J Low Genit Tract Dis 2013 Oct;17(4):404-8

1Sackler School of Medicine, Tel Aviv, Israel; 2Department of Surgery, Mount Sinai School of Medicine, New York, NY; and 3Qiagen Gaithersburg, Inc., Gaithersburg, MD.

Objective: The incidence of anal human papillomavirus (HPV) infection and of HPV-related disease in men who have sex with men continues to rise. Screening procedures can be uncomfortable and may lead to decreased patient compliance. We endeavored to determine the tolerability of screening procedures for anal HPV disease.

Materials And Methods: This was a 2-visit screening study. On visit 1 (V1), cells for cytology (using a swab) and HPV testing (randomized to a brush or swab) were collected, followed by digital rectal examination and standard anoscopy. At visit 2 (V2), patients had repeated HPV sampling (brush or swab) and high-resolution anoscopy with biopsy where indicated. Patients reported discomfort of procedures (0-5) and complications.

Results: Visit 1 standard anoscopy caused the most discomfort (mean = 1.90). Visit 2 biopsy caused the least discomfort (mean = 1.04). The mean discomfort difference between V1 HPV sampling with swab (1.56) and brush (1.86) was significant (p = .03) but not at V2. The mean difference between V2 HPV brush (1.63) and V1 brush (1.86) discomfort was significant (p = .02), but there was no significant difference for V1 and V2 swab. There was no discomfort difference between standard anoscopy and high-resolution anoscopy (p = .14). All patients who reported at V1 that the discomfort would prevent them from having procedure again returned for V2. There was no significant difference in bleeding or pain after V1 for brush or swab.

Conclusions: Screening procedures for anal HPV-related disease were well tolerated, and no single procedure or HPV sampling device reduced patient compliance.
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http://dx.doi.org/10.1097/LGT.0b013e31827fb76cDOI Listing
October 2013

Sexually transmitted infections as a cause of proctitis in men who have sex with men.

Dis Colon Rectum 2009 Mar;52(3):507-12

Department of Surgery, Mount Sinai School of Medicine, New York, New York, USA.

Purpose: Many men who have sex with men (MSM) present with complaints of bleeding, pain, and inflammation. We endeavored to determine the incidence of sexually transmitted infections in MSM referred for treatment of these symptoms and the effect of empiric therapy.

Methods: A retrospective chart review of all MSM seen in 2007 at one surgical practice diagnosed with presumptive proctitis was performed. All MSM are routinely tested for sexually transmitted infections.

Results: Twenty-six MSM were identified (mean age, 38 years), and 17 (65 percent) were HIV+. Bleeding and pain were the most common complaints seen in 19 (73 percent) and 16 (62 percent), respectively. The most common findings were discharge in 15 (58 percent) and blood in 14 (54 percent). Sexually transmitted infections were identified in 21 (86 percent) and 3 (11 percent) had unidentified etiology. Gonorrhea was found in eight (43 percent), herpes simplex virus in six (29 percent), lymphogranuloma venereum in four (19 percent), and two each (10 percent) had Chlamydia and syphilis. Three had multiple infections. All but two treated empirically responded without complication and they had Crohn's colitis (n = 1) and rectal lymphoma (n = 1).

Conclusions: Sexually transmitted infections are a common cause of proctitis and appropriate testing is imperative. Lymphogranuloma venereum is a common cause. Empiric treatment leads to rapid resolution and diminishes the chance for spread.
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http://dx.doi.org/10.1007/DCR.0b013e31819ad537DOI Listing
March 2009

Detection of oncogenic human papillomavirus and other predictors of anal high-grade dysplasia in men who have sex with men with abnormal cytology.

Dis Colon Rectum 2009 Jan;52(1):31-9

Department of Surgery, Mount Sinai School of Medicine, New York, New York, USA.

Purpose: The incidence of anal high-grade dysplasia in men who have sex with men is increasing. Anal cytology that shows atypical squamous cells of undetermined significance is common, nonspecific, and rarely predicts high-grade squamous intraepithelial lesion. We want to know whether Hybrid-Capture II(R) testing for oncogenic human papillomavirus (human papillomavirus+) in men who have sex with men with atypical squamous cells of undetermined significance is beneficial and whether other predictors of high-grade squamous intraepithelial lesion exist.

Methods: We performed a retrospective chart review of men who have sex with men undergoing anal screening with atypical squamous cells of undetermined significance cytology, Hybrid-Capture(R) II testing, and biopsy. Records were analyzed for all screenings.

Results: A total of 597 men who have sex with men enrolled and had 1,015 atypical squamous cells of undetermined significance cytology results: 185 (18.2 percent) had high-grade squamous intraepithelial lesion and 156 (84 percent) were human papillomavirus+. The rates for sensitivity, specificity, positive predictive value, and negative predictive value were 84, 53, 29, and 94 percent, respectively. Of 390 low-grade squamous intraepithelial lesion cytology results, high-grade squamous intraepithelial lesion was found in 141 and 127 (90 percent) were human papillomavirus+. Those with previous high-grade squamous intraepithelial lesions or human immunodeficiency virus had increased risk of high-grade squamous intraepithelial lesion (hazard ratio = 2.2 and hazard ratio = 1.95, respectively). Age was not a factor.

Conclusions: Hybrid-Capture II(R) testing is useful in men who have sex with men with atypical squamous cells of undetermined significance. Referring only those with oncogenic human papillomavirus for biopsy reduces the number requiring this by almost half but some high-grade squamous intraepithelial lesions are missed. History of high-grade squamous intraepithelial lesion and human immunodeficiency virus are predictors of high-grade squamous intraepithelial lesion while screening intervals might be lengthened absent oncogenic human papillomavirus or in those free of high-grade squamous intraepithelial lesion for long periods.
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http://dx.doi.org/10.1007/DCR.0b013e31819736aaDOI Listing
January 2009